Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, primarily due to most cases being diagnosed at an advanced, incurable stage. While 5-year survival of metastatic PDAC is <5%, outcomes dramatically improve for localized PDAC. Poor prognosis is due to a lack of biomarkers for diagnosing PDAC at an early, asymptomatic stage when cure is possible. Effective diagnosis of early stage PDAC depends on identification of accurate, non-invasive biomarkers in combination with a strategy for screening increased-risk populations. Discovery of blood-based biomarkers that accurately detect PDAC in increased-risk populations before it becomes invasive would transform management of patients who develop PDAC and will also improve our understanding of molecular events leading to PDAC development. Our primary objective is to identify non- invasive protein biomarkers in plasma and exosomes/extracellular microvesicles (EMV) that accurately distinguish between patients with and without advanced PDAC. To improve on prior biomarker discovery efforts that have failed to deliver early detection markers of clinical utility, we will apply a cutting edge highly multiplexed, high sensitivity biomarker discovery technology, SOMAscan, measuring simultaneously expression of 1305 proteins across the whole dynamic range. Our central hypothesis that SOMAscan will yield new, PDAC-specific plasma and EMV protein biomarkers for detection of PDAC at an earlier stage when cure is likely and will generate novel findings that cannot be derived by other methods is based on our strong preliminary data that provide solid evidence as to the potential for SOMAscan to identify novel, low abundance, high accuracy blood-based PDAC biomarkers and new pathways not previously linked to PDAC. To identify such PDAC-specific biomarkers we will apply SOMAscan followed by preliminary independent ELISA validation to plasma and EMVs from patients with localized PDAC, chronic pancreatitis and matched healthy controls as well as longitudinal samples from new onset diabetics. Our ultimate goal is to develop robust non- invasive plasma or EMV diagnostics to assess the risk of malignant potential of PDAC precursor lesions and to develop screening approaches for early detection of PDAC in increased-risk subjects. Our Specific Aims are: Aim 1. Define candidate plasma protein biomarkers for PDAC using ultra-sensitive SOMAscan Aim 2. Define candidate EMV protein biomarkers for PDAC using ultra-sensitive SOMAscan Impact: Upon completion of this study we will have characterized candidate plasma and exosome protein biomarkers that accurately detect early stage PDAC and generated a clinical algorithm for recognizing early stage PDAC. Our study is highly relevant as biomarkers capable of pre-symptomatic PDAC diagnosis and identification of key PDAC-linked pathways will fundamentally advance our understanding of PDAC pathogenesis and may ultimately transform PDAC detection and management.